tbuckley/cabot-search huggingface dataset:
Abstract P2-24-05: TAVO412 - A Novel Trispecific cMet x EGFR x VEGF Antibody for Triple Negative Breast Cancer
Authors: Mark Chiu
Journal: Cancer Research (2023)

Abstract Novel Multispecific Antibody with Superior Activity in TNBC INTRO: TNBC (Triple Negative Breast Cancer) has a diverse etiology and high unmet need. We created a novel multispecific antibody with unique 2:1:1 ratio of EGFR:cMet:VEGF binding arms with excellent activity against TNBC. METHOD: Multiple in vitro EGFR &amp; cMet signaling pathway inhibition, proliferation inhibition, and ADCC, ADCP, and CDC were conducted. Various in vivo studies using the TNBC cell lines (MDA-MB-468, MDA-MB-231, HCC70, BT20) with diverse levels of EGFR and cMet receptor density levels were tested. RESULTS: Strong tumor growth inhibition was found in multiple TNBC animal models (56% tumor growth inhibition (TGI) in BT20, 26% TGI in HCC70, 62% TGI in MDA-MB-231). Tavo412 demonstrated better activity than comparator molecules in several in vivo models using lung, gastric, and pancreatic cancer cell lines (data not shown). A one month GLP toxicity study in cynomolgus monkeys has been completed with well-expected tolerability and pharmacokinetic profiles. Besides shutting down three important cancer pathways, TAVO412 showed high potency because it also has strong EGFR and VEGF binding at pH 6 in the tumor microenvironment. Moreover, Tavo412 has exemplary Fc effector function engaging the innate immune responses that include ADCC, ADCP, and CDC. There is also a synergistic tumor growth inhibition in the presence of a standard of care molecule such as doxorubicin (61% in HCC70 with TAVO412 + doxorubicin, 66% TGI in BT20 with TAVO412 + doxorubicin, 71% TGI in MDA-MB-231 with TAVO412 + doxorubicin). In addition, gastric, pancreatic, and lung cancer in vivo models showed excellent TGI profiles. CONCLUSIONS: Tavo412 has the potential activity to be a superior multispecific antibody to treat patients with triple negative breast cancer. Phase 1 clinical testing in patients is anticipated in early 2023. Citation Format: Mark Chiu. TAVO412 - A Novel Trispecific cMet x EGFR x VEGF Antibody for Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-05.
Abstract ED7-4: Beyond the lab: Clinical implications
Authors: Christina Curtis
Journal: Cancer Research (2023)

Abstract During this talk, I will review the ever expanding repertoire of single cell and spatially resolved profiling techniques which enable the interrogation breast cancer pathlogy, immuno-biology and treatment response at unprecedented resolution. I will outline considerations for throughput, plex and resolution across different methods before providing several case studies in their application. As one example, I will outline the use of multi-omic single cell profiling and spatial proteomic profiling to characterize changes throughout the course of neoadjuvant Her2-targeted therapy and leading to the identification of candidate predictive biomarkers. I will go on to discuss translational and potential clinical applications of these techniques. Citation Format: Christina Curtis. Beyond the lab: Clinical implications [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED7-4.
Abstract ED11-2: HER2 positive breast cancer
Authors: Luca Gianni, Giampaolo Bianchini
Journal: Cancer Research (2023)

Abstract Neoadjuvant therapy of HER2+ breast cancer has been groundbreaking. It showed the superior results in terms of pathologic complete response (pCR) and event free survival (EFS) of adding trastuzumab to chemotherapy in women with locally advanced breast cancer (NOAH trial) that led to the first regulatory approval of a neoadjuvant approach in the field of breast cancer. In addition, neoadjuvant studies (NeoSphere, neoALLTO) clearly showed the improved antitumor activity of dual blockade of the HER2 receptor, paved the way to the Aphinity adjuvant study and justified the current worldwide use of dual black of HER2 in high/moderate risk HER2+ early breast cancer. In the above scenario the design and results of the Katherine study were a landmark achievement. By proving the clinical value of shifting treatment from trastuzumab to trastuzumab-DM1 in women with residual disease after neoadjuvant therapy the study provided firm clinical evidence that residual disease can be used as a surrogate of relative resistance that per se justifies the adoption of alternative non cross resistant regimens/therapies at the individual level. The clinical success of neoadjuvant trials in HER2+ early breast cancer went hand-to-hand with translational studies that that are identifying markers predicting for pCR and EFS that are and will be used to fine tuning a more individually tailored approach to treatment, and eventually effective and safe de-escalation strategies. The rich collection of neoadjuvant studies that shaped the modern approach to treatment of women with early HER2+ breast cancer will be enriched of studies with new drugs, trastuzumab deruxtecan and tucatinib to name some of the front runners. All current and future treatments will greatly depend on the neoadjuvant approach as a tool for a quick assessment of the clinical value of new therapies. Such approach has so far been used as basis or supporting evidence for regulatory approvals worldwide, based on the concept that pCR can be viewed as surrogate of long-term benefit. Individual trials and meta-analyses are challenging the dependability of pCR to predict EFS at trial level. However, the benefits of tumor eradication (pCR) at individual level continue to support the simple clinical concept that more pCR is better and that regimens leading to it deserve full credit. Acknowledgment: The work of Luca Gianni is supported by grants of the BCRF Citation Format: Luca Gianni, Giampaolo Bianchini. HER2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED11-2.
Disease-free Survival Analysis for Patients with High-risk Muscle-invasive Urothelial Carcinoma from the Randomized CheckMate 274 Trial by PD-L1 Combined Positive Score and Tumor Cell Score
Authors: Matthew D. Galsky, Dean F. Bajorin, Johannes Alfred Witjes, Jürgen E. Gschwend, Yoshihiko Tomita, Federico Nasroulah, Jun Li, Sandra Collette, Begoña P. Valderrama, Marc-Oliver Grimm, Leonard Appleman, Gwenaelle Gravis, Andrea Necchi, Dingwei Ye, Frank Stenner, Megan Wind-Rotolo, Joshua Zhang, Keziban Ünsal-Kaçmaz
Journal: European Urology (2023)

The CheckMate 274 trial demonstrated improved disease-free survival (DFS) with adjuvant nivolumab versus placebo in patients with muscle-invasive urothelial carcinoma at high risk of recurrence after radical surgery in both the intent-to-treat population and the subset with tumor programmed death ligand 1 (PD-L1) expression ≥1%. To analyze DFS by combined positive score (CPS), which is based on PD-L1 expression in both tumor and immune cells. We randomized a total of 709 patients 1:1 to nivolumab 240 mg or placebo every 2 wk intravenously for ≤1 yr of adjuvant treatment. Nivolumab 240 mg. Primary endpoints were DFS in the intent-to-treat population and patients with tumor PD-L1 expression ≥1% using the tumor cell (TC) score. CPS was determined retrospectively from previously stained slides. Tumor samples with both quantifiable CPS and TC were analyzed. Of 629 patients evaluable for CPS and TC, 557 (89%) had CPS ≥1, 72 (11%) had CPS <1, 249 (40%) had TC ≥1%, and 380 (60%) had TC <1%. Among patients with TC <1%, 81% (n = 309) had CPS ≥1. DFS was improved with nivolumab versus placebo for patients with TC ≥1% (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.35–0.71), those with CPS ≥1 (HR 0.62, 95% CI 0.49–0.78), and patients with both TC <1% and CPS ≥1 (HR 0.73, 95% CI 0.54–0.99). More patients had CPS ≥1 than TC ≥1%, and most patients who had TC <1% had CPS ≥1. In addition, patients with CPS ≥1 experienced improved DFS with nivolumab. These results may, in part, explain the mechanisms underlying a benefit with adjuvant nivolumab even in patients who had both TC <1% and CPS ≥1. We studied survival time without cancer recurrence (disease-free survival; DFS) for patients treated with nivolumab versus placebo after surgery to remove the bladder or components of the urinary tract for bladder cancer in the CheckMate 274 trial. We assessed the impact of levels of the protein PD-L1 expressed either on tumor cells (tumor cell score; TC) or on both tumor cells and immune cells surrounding the tumor (combined positive score; CPS). DFS was impoved with nivolumab versus placebo for patients with TC ≥1%, CPS ≥1, and for patients with both TC <1% and CPS ≥1. This analysis may help physicians understand which patients would benefit most from treatment with nivolumab.
Abstract P2-24-01: The development of covalent microtubule stabilizers for drug-resistant cancers
Authors: Jacob N. Essif, April Risinger
Journal: Cancer Research (2023)

Abstract Microtubule targeting agents (MTAs) are some of the most commonly used and effective chemotherapeutic agents used in the treatment of breast cancer and other solid tumors. Clinically approved MTAs include microtubule destabilizers, such as the vinca alkaloids or eribulin, as well as the taxane class of microtubule stabilizers, including paclitaxel. While MTAs are effective chemotherapeutics, the development of resistance due to drug efflux or changes in β-tubulin isotype expression are major clinical limitations to each the currently approved drugs of this class. One strategy for overcoming drug resistance is the development of drugs that covalently bind to their drug target, which has been validated in the clinic with the success of irreversible EGFR inhibitors in drug resistant non-small cell lung cancer. We have identified the C22,23-epoxytaccalonolides (taccas) as a class of plant-derived microtubule stabilizers that covalently bind to β-tubulin with a high degree of specificity and retain efficacy in drug-resistant models in vitro and in vivo. Although the taccas have potent and persistent antitumor efficacy in vivo, they suffer from a narrow therapeutic index and short serum half-life that provides optimal efficacy when targeted directly to the tumor site. We are undertaking a multipronged approach to generate synthetic tacca analogs (taccalogs) that retain the efficacy of the natural product with improved pharmacokinetic properties, including improved serum binding, to increase half-life and provide better in vivo tolerability. We are also identifying strategies to improve tumor targeting of the taccas, which is being guided by determining their in vivo distribution with radiolabeled analogs. In a complementary approach, we tested the hypothesis that non-covalent microtubule stabilizers that have increased binding affinity to tubulin share properties with the taccas, such as the ability to circumvent drug resistance and provide potent and persistent in vivo efficacy with a more tolerable therapeutic window. Our data suggest that while non-covalent microtubule stabilizers with improved binding compared to paclitaxel provide improved cellular persistence after drug washout and potent antitumor efficacy, they are not able to overcome drug resistance to some degree as covalent inhibitors, demonstrating the advantage of continuing to develop irreversible drugs such as the taccalonolides for the treatment of drug resistant disease. Citation Format: Jacob N. Essif, April Risinger. The development of covalent microtubule stabilizers for drug-resistant cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-01.
Abstract ED3-3A: Mechanisms of resistance
Authors: Leif Ellisen
Journal: Cancer Research (2023)

Abstract Antibody Drug Conjugates (ADCs) are emerging as promising therapeutics for all subtypes of breast cancer. ADCs are composed of a monoclonal antibody directed against a tumor-expressed antibody, conjugated via a variety of linker chemistries to a cytotoxic or other tumor-active payload. Tumor-selective drug delivery via ADCs has the potential to substantially improve the therapeutic window and efficacy for a variety of therapeutic agents. Indeed, recent clinical data have demonstrated significant improvements in overall survival with the use of single-agent ADCs across the spectrum of advanced breast cancer. However, both de novo and acquired resistance to ADCs is common, and may involve a diverse array of potential mechanisms that reflect the complexity of ADC action. These include alteration or downregulation of the ADC target, deregulation of intracellular trafficking or endolysosomal processing of the internalized ADC, and a variety of payload-specific mechanisms of resistance such as induction of drug efflux or activation of cell survival pathways. Which mechanism(s) dominates in a given setting may depend on both ADC-specific and tumor-specific factors. For example, linker design is likely to have a major influence on potential ADC resistance: ADCs with a non-cleavable linker (e.g. trastuzumab emtansine) are dependent upon fusion with acidified lysosomes for degradation and payload release, and attenuated acidification has been demonstrated pre-clinically as a resistance mechanism. In contrast, ADCs with a cleavable peptide linker (e.g. trastuzumab deruxtecan) may not require lysosomal processing for payload release. Furthermore, highly genetically unstable tumors may simultaneously generate multiple types of resistance mechanisms. We recently demonstrated the emergence of distinct acquired resistance mutations to sacituzumab govitecan, involving the ADC antibody target (TROP2) and the payload target (topoisomerase 1), within different metastatic lesions of an individual patient. General strategies to overcome ADC resistance include the sequential use of multiple ADCs, and/or the up-front use of select combination therapies incorporating ADCs. Clearly, the success of these approaches will require a more thorough evaluation and understanding of resistance mechanisms as they occur in patients. Fortunately, the relative success of ADCs for breast cancer treatment to date is spurring the identification of new targets, approaches for linker design, and a wide diversity of payloads that will be instrumental for efforts to overcome resistance. Citation Format: Leif Ellisen. Mechanisms of resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED3-3A.
Abstract MS2-2: Extra cellular matrix and dormancy
Authors: Jose Javier Bravo-Cordero
Journal: Cancer Research (2023)

Abstract Breast cancer metastasis develops from disseminated cancer cells (DCCs) that leave the primary tumor and seed in distant organs. In those organs, DCCs undergo a period of dormancy during which cancer cells remain occult, in a non-proliferative state, before metastases become detectable. In this seminar I will discuss how disseminated cancer cells enter in dormancy at metastatic sites and the importance of the ECM in this process. We have found that dormant cancer cells express a specific set of ECM genes, "the matrisome", that is lost upon break from dormancy. ECM proteomics identify tumor-derived COL3A1 as a key ECM component required for tumor cell dormancy at metastatic organs. Intravital imaging and SHG microscopy reveals that the dormancy-to-reactivation transition is accompanied by changes in collagen three-dimensional architecture. Our data reveal a novel barrier to metastasis through a mechanism by which DCCs depend on the assembly of a pro-quiescence ECM to establish a niche that sustains dormancy. Citation Format: Jose Javier Bravo-Cordero. Extra cellular matrix and dormancy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr MS2-2.
Abstract ED13-3: Cardiovascular toxicity and breast cancer: Detection and prevention strategies
Authors: Dinesh Thavendiranathan
Journal: Cancer Research (2023)

Abstract The presentation will discuss the potential cardiovascular toxicities (e.g., heart failure, coronary artery disease, arrhythmias) that are seen in women with breast cancer with a particular focus on those receiving cancer therapy. It will discuss the associated drugs, timing, the severity, and treatment options. The presentation will also include strategies that could be considered for risk stratification of patients prior to initiation of cancer therapy, methods to identify early cardiovascular injury, and primary prevention options. Recent guidelines including the ESC cardio-oncology guidelines and the prior ASCO guidelines will be highlighted. Practical approaches to assessment and management of cardiovascular toxicities will also be discussed. The presentation will wrap up providing potential future directions in the field. Citation Format: Dinesh Thavendiranathan. Cardiovascular toxicity and breast cancer: Detection and prevention strategies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED13-3.
Abstract ED12-3: ATR inhibitors and PARP1 selective PARP inhibitors
Authors: Andrew Tutt
Journal: Cancer Research (2023)

Abstract The targeting of Homologous Recombination deficient (HRD) malignancy using a synthetic lethal strategy based on the inhibition and trapping of PARP1 on DNA in manner that leads to tumour selective effects via dependency on the function of HR gene products such as BRCA1, BRCA2 and PALB2 for DNA replication fitness is now well established. However, there is a need to improve both the frequency and duration of response in the licensed indications and to explore combination PARP inhibitor (PARPi) strategies that may be effective a broader range of breast cancers with functional deficiencies in HR and the wider DNA damage response. ATR inhibitors exacerbate replication stress that is toxic to HR deficient cells. Combinations of an ATR inhibition (ATRi) and PARPi have been shown to be synergistic and to be active in PARPi resistant pre-clinical model contexts. The development of combination strategies of these agents and of platinums and ATRi have been limited by combinatorial toxicity but have recently reported results in breast cancer. PARP1 is part of a family of PARP enzymes and currently licensed PARPi inhibit several family members that underpin some of their toxicity. New PARP1 selective agents have recently reported results in early phase trials. I will review some of the mechanistic rationale, preclinical data and relevant clinical trial data in my lecture. Citation Format: Andrew Tutt. ATR inhibitors and PARP1 selective PARP inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED12-3.
Abstract P1-05-03: Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study
Authors: Joanne Mortimer, Sidney S. Lindsey, Ilana Solomon, Wai Park, Duveen Sturgeon, Kathleen Blazer, Stacy Gray, Joseph Bonner, Xiaoyu Xia, Stephen Gruber
Journal: Cancer Research (2023)

Abstract Table 1. Incidence of BRCA 1 and 2 mutations by Race and Ethnicity BRCA1 BRCA2 BRCA1 or 2 VUS/Negative Native American 0 1 1 6 Asian 2 3 5 150 Black/African American 3 2 5 48 Native Hawaiian or Pacific Islander 0 0 0 5 Other 1 1 1* 26 White 25 17 42 688 Unknown 0 0 0 20 Declined 1 0 1 24 TOTAL 32 24 55 967 * Patient had both BRCA1 and BRCA2 mutations Citation Format: Joanne Mortimer, Sidney S. Lindsey, Ilana Solomon, Wai Park, Duveen Sturgeon, Kathleen Blazer, Stacy Gray, Joseph Bonner, Xiaoyu Xia, Stephen Gruber. Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-03.
Abstract CC1-1-1: To clip or not to clip (Part 1)
Authors: Abigail Caudle
Journal: Cancer Research (2023)

Abstract Clinically node positive breast cancer patients often recieve neoadjuvant chemotherapy which can eradicate nodal disease. While sentinel node dissection alone has been shown to predict treatment response with a false negative rate of 12-14%, it is possible to increase the accuracy by performing targeted axillary dissection (TAD). To perform TAD, a clip is placed in a node if biopsy confirms disease. The procedure then involves selectively localizing and removing the clipped node in addition to the sentinel nodes. Multiple studies have show that this approach has a false negative rate of &amp;lt;5%. These studies also show that the clipped node is not retrieved as a sentinel node in &amp;gt; 20% of cases. This means that evaluating the sentinel nodes alone would miss evaluating the node with confirmed disease in a significant proportion of patients. This session will focus on the question of whether there is benefit to placing clips in nodes and ensuring removal after neoadjuvant chemotherapy. Citation Format: Abigail Caudle. To clip or not to clip (Part 1) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr CC1-1-1.